Dietary vaccine for inhibiting metabolism of methanol

ABSTRACT

Apparatus and a method for inhibiting the metabolism of methanol in a human. The apparatus comprises carrier means for a source of ethanol. The carrier means, when combined with a source of ethanol and introduced in the digestive tract of a human being, permits the gradual time release of ethanol from the dietary vaccine into the digestive tract for absorption into the blood stream of an individual. The method comprises introducing the ethanol charged carrier means in the digestive tract of an individual.

This invention pertains to apparatus and methods for preventing inhumans the metabolism of methanol to form the toxic metabolitesformaldehyde and formic acid.

More particularly, the invention pertains to a benign metabolic dietaryvaccine which can be introduced at any point in the digestive tract ofan individual to protect the individual from blindness, other visualdisturbances, neuritis, headaches, dizziness, severe depression,myocardial hypertrophy and activation of the reticuloendothelial systemwhich can result from the metabolism of methanol by the body.

In a further respect, the invention pertains to a dietary vaccine which,by continually releasing in the digestive tract minor effective amountsof an anti-metabolic substance which is absorbed into the blood stream,protects an individual from various pollutant sources of methanol.

Methanol is one of the most widespread, insidious toxicants encounteredin modern civilization. Common sources of methanol are liquor, cigarettesmoke, fumes from gasoline to which methanol has been added to increaseoctane, ditto machines, and Nutrasweet®. Nutrasweet®, the new artificialsweetner which is a generally accepted substitute for saccharine, is asmall molecule made up of three components: Phenylalanine, asparticacid, and methanol (wood alcohol). Methanol may be derived in someindividuals from metabolic processes involving intestinal flora. Forinstance, the action of Pectin-methylesterase on dietary pectins, canliberate methanol.

Methanol is a toxicant which has no therapeutic properties. Theingestion of two teaspoons can be lethal in humans. Methyl alcoholproduces the Methyl Alcohol Syndrome, consistently, only in humans andin no other animal. There is a clear difference between "toxicity",which can be produced in every living thing, and the methyl alcohol"toxic syndrome". The greater toxicity of methanol to man is deeplyrooted in the limited biochemical pathways available to humans fordetoxification. The loss of uricase (EC 1.7.3.3.),formyl-tetrahydrofolate synthetase (EC 6.3.4.3) and other enzymes duringevolution sets man apart from all animals including the monkey. Humanssuffer "toxic syndrome" at a minimum lethal methanol dose of less than 1gm/kg, much less than that of monkeys, 3-6 gm/kg.

The United States Environmental Protection Agency in their MultimediaEnvironmental Goals for Environmental Assessment recommends a minimumacute toxicity concentration of methanol in drinking water at 3.9 partsper million, with a recommended limit of consumption below 7.8 mg/day.This report clearly indicates that methanol:

". . . is considered a cumulative poison due to the low rate ofexcretion once it is absorbed. In the body, methanol is oxidized toformaldehyde and formic acid; both of these metabolites are toxic."

The most characteristic symptons of methyl alcohol poisoning in humansare the various visual disturbances which can occur. These symptomsinclude misty vision, progressive contraction of visual fields (tunnelvision), mist before the eyes, blurring of vision, and obscuration ofvision. Other methyl alcohol poisoning symptoms include headache, earbuzzing, dizziness, nausea, unsteady gait, gastrointestinaldisturbances, weakness, vertigo, chills, memory lapses, behavioraldisturbances, neuritis, and numbness and shooting pains in the lowerextremities, hands and forearms. In fata cases, the liver, kidneys andheart may show parenchymatous degeneration, while the lungs showdesquamation of epithelium, emphysema, edema, congestion and bronchialpneumonia.

Ethanol is well known as a desperate cure for severe cases of methanolpoisoning. The ethanol is administered intravenously in substantialamounts sufficient to inhibit the metabolism of methanol to formaldehydeand formic acid. The amounts of ethanol intravenously administered are,alone, sufficient to cause intoxication of the patient, but this effectis accepted in order to prevent the death of or severe injury to thepatient.

When ethanol is present in the body together with methanol, the bodygenerally first selectively metabolizes the ethanol, permitting the bodyto remove methanol through the lungs and urine. However, ifconcentration of ethanol in the body is too low, the body can metabolizemethanol into formaldehyde and formic acid.

Most individuals do not ingest lethal amounts of methanol over shortperiods of time but are, during their lifetime, instead exposed todietary and environmental sources containing moderate or small amountsof methanol. Since methanol is a cumulative toxin, such sources pose athreat to the physical well being of an individual. For example, anaverage aspartame-sweetened beverage has an aspartame content of about555 mg/liter, and, therefore, has a methanol content of 56 mg/liter (56ppm). If a child weighing twenty five kilograms consumes on a warm day,after exercising, two-thirds of a two-liter bottle of soft drinksweetened with aspartame, that child consumes over 732 mg of aspartame(29 mg/kg). This alone exceeds the safe daily aspartame consumptionlevel specified by the Food and Drug Administration. The child wouldabsorb over 70 mg of methanol from the soft drink. This is almost tentimes the Environmental Protection Agency's recommended daily limit ofconsumption for methanol.

There is apparently presently no method for protecting an individualfrom the metabolism of cumulative minimal amounts of environmentalmethanol pollutants daily ingested into the body. The intravenousadministration of ethanol is acceptable in severe cases of methanolpoisoning because of the desperateness of such cases. Suchadministration of ethanol is not feasible under normal day-to-day livingcircumstances because of the intoxicating effect of ethanol and becauseof the impracticality of repeated intravenous administration of asubstance. Further, in order to provide ethanol protection in the bodyfor a reasonable period of time after the intravenous administration ofethanol, an intoxicating concentration of ethanol must be directed intothe blood stream.

Oral consumption of ethanol is not a desirable method for treatingmethanol poisoning because it is difficult to control the rate thatethanol is absorbed in the blood stream, and because, unless a containerof ethanol is constantly carried on the person, an intoxicating amountof ethanol must be consumed to protect a person for a reasonable periodof time after ethanol has been ingested.

Therefore, it would be highly desirable to provide a method forprotecting an individual from methanol which he or she daily ingestsfrom dietary and environmental pollutant sources, and which could bereadily implemented by an individual without requiring the utilizationof catheters or other medical equipment.

It would also be highly desirable to provide a method which would, aftera single use, provide an individual over an extended period of time withcontinuous protection from ingested methanol.

I have discovered a new metabolic dietary vaccine composition and methodfor administering the composition which enables an individual to readilyprotect himself from methanol ingested or inhaled from variousenvironmental pollutant sources. The dietary vaccine compositioninhibits the metabolism of methanol by the body to form formaldehyde andformic acid. The composition comprises a source of ethanol and carriermeans for the ethanol source. The carrier means permits the gradualrelease over time of ethanol into the digestive tract of an individual.The ethanol is released in minor effective amounts sufficient to inhibitthe metabolism of methanol in the body and sufficient to avoidintoxicating the individual.

In another embodiment of the invention, I provide a method forpreventing the metabolism of methanol in the body to form formaldehydeand formic acid. The method comprises the steps of introducing in thedigestive tract of an individual a dietary vaccine comprising a sourceof ethanol and carrier means, the carrier means permitting the gradualrelease of ethanol into the digestive tract in minor effective amountssufficient to inhibit the metabolism of methanol in the body andsufficient to avoid the intoxication of the individual by the ethanol.

It is presently preferred that the carrier means release ethanol intothe digestive tract at a rate sufficient to maintain a concentration ofethanol in the blood stream generally in the range of ten to fifty partsper million (ppm). However, the release of ethanol from the carriermeans can be at a rate sufficient to maintain a concentration of one totwo hundred and fifty parts per million ethanol in the blood stream. Ifethanol is released from the carrier means at a rate sufficient tomaintain a concentration in the blood stream of greater than 1,000 ppm,the individual will probably become intoxicated. If the concentration ofethanol in the blood stream is greater than 200-700, then methanolgenerally is not removed from the body through the urine and breath.

The source of ethanol can be administered into the digestive tract fromwithin carrier means comprising a capsule having a dialytic wall withpores which permit ethanol carried in the capsule to slowly bleedthrough the pores into the digestive tract. The ethanol can be mixedwith propylene glycol, glycerol, water, potassium or sodium stearate(which is known to deactivate pectin-methylesterase) or other solid orliquid substances which function as carrier means to slow or increasethe rate of diffusion of ethanol through the dialytic wall of thecapsule. The capsule can be orally, suppositorally, or surgicallyintroduced in the digestive tract. The dialytic wall of the capsulepresently preferably comprises a cellophane or polycarbonate film havingpores approximately 10 Angstroms in diameter. The width of each poreopening can vary, but is preferably in the range of 5 to 30 Angstroms.The dialytic film or wall is preferably resistant to degradation by thedigestive system for a period of time necessary to permit all or nearlyall of the ethanol carried within the dialytic film to gradually bleedthrough the pores into the digestive tract.

In certain cases, the wall of the capsule or carrier means can berapidly destroyed by the digestive system. For instance, a solution ofethanol could be mixed or chemically combined or bound with a thickeneror some other carrier composition which would slow the release ofethanol into the digestive tract. In this instance, the capsule wall orcoating enclosing the ethanol mixture need not be dialytic or resistanceto digestive system fluids, but could be comprised of a gelatin whichwould rapidly dissolve in the digestive tract to release theethanol--thickener mixture.

The membrane wall or film encapsulating a source of ethanol ispreferably comprised of a physiologically nontoxic material. Sinceethanol is volatile and rapidly evaporates when exposed to theatmosphere, capsules carrying ethanol are, prior to being stored forlater use, preferably coated with a material which prevents or slowsevaporation of ethanol into the atmosphere. Alternatively, the capsulescan be stored in a container which maintains a vapor pressure equal toor greater than that of the ethanol, or, may be stored in a solutionwhich has equivalent ethanol content and which does to tend to breakdown or alter the chemical composition of the ethanol source and itscarrier means.

When the carrier capsule or tablet is administered orally, it may bedesirable that it be coated with an enteric substance so the capsulewill not be destroyed prior to its reaching the lower intestinal tract.If a capsule or tablet having a dialytic film is not utilized and asource of ethanol is simply mixed or chemically combined with a carriersubstance which slows the release of ethanol in the intestinal tract,then it is preferred that the ethanol source--carrier substance mixturebe resistant to stomach digestive chemicals so the ethanol will not becompletely released in the stomach.

Ethanol is readily absorbed into the body at any point along thedigestive tract, including the stomach lining and large and smallintestines. Therefore, the carrier means can be formed to permit thegradual release of ethanol during the entire time period required forthe ethanol dietary vaccine to traverse the digestive tract.

The dietary vaccine composition of the invention permits the gradualcontrolled release into the blood stream of minor effective amounts ofethanol which act to prevent the metabolism of methanol and which, atthe same time, are not either sufficient to cause intoxication of anindividual or sufficient to prevent methanol from being removed by thebody through the breath and urine. The dietary vaccine composition ofthe invention can be readily ingested by an individual without requiringthe utilization of intravenous or other medical equipment.

An alcohol such as ethanol has never been combined with a time releasecarrier means.

An alcohol such as ethanol has never been introduced into the digestivetract of an individual for gradual release therealong as a dietaryvaccine.

An alcohol such as ethanol has never been utilized as a universalpreventitive to protect an individual from all environmental sources ofpollutant methanol.

In use, a source of ethanol is combined with time release carrier meansand is introduced into the digestive tract of an individual. After theethanol--time release carrier means unit has been introduced in thedigestive tract and a sufficient amount of time has passed for thedesired portion of all of the ethanol carried in the unit to be releasedinto the intestine, another ethanol--carrier means unit can beintroduced in the digestive tract of an individual. Units can beintroduced in the digestive tract as often as necessary to keep theconcentration of ethanol in the blood stream at a selected level.

A particular advantage of the invention is that it provides--with asingle administration of an ethanol--carrier means capsule or unit, anextended period of protection from metabolism by the body of methanol.

Sources of ethanol include ethyl alcohol, ethyl esters of variouschemicals--for example pectin ethylester--that metabolize in the body insuch a way as to slowly liberate ethanol upon clevage of the ethylester, and include microorganisms that can survive within a dialyticcapsule or other ethanol source carrier means and either convert throughfermentation various dietary carbohydrates into ethanol or otherwiseproduce ethanol through the microorganisms' own metabolic processes.

As used herein, the term "apparatus" refers to liquid, semi-liquid,and/or solid material carrier means utilized to carry ethanol into thedigestive tract of an individual and release over time the ethanolcarried by the carrier means. For example, the capsules described inExamples 5 to 10 comprise apparatus or carrier means constructed andused in accordance with the invention.

As used herein, the term "dietary" refers to a composition or apparatuswhich is, in use, introduced in the stomach and/or intestinal tract ofan individual.

The following examples are presented, not by way of limitation of thescope of the invention, but to illustrate to those skilled in the art,the practice of various of the presently preferred embodiments of theinvention and to distinguish the invention from the prior art.

EXAMPLE 1

A 43 year old male subject, five feet seven inches high, weighing 220pounds, had complained of severe headaches, vertigo, nausea and blurringof vision within hours of consumption of a can of diet soft drinkcontaining NUTRASWEET sweetener. NUTRASWEET is an artificial sweetenerwhich releases approximately 10% by weight of methanol during digestion.The subject was in good health and was not taking any prescription drugsor other medications. When the subject consumed twelve ounces ofsaccharine sweetened fluid, the subject did not exhibit the headachesand other adverse symptoms noted above. The subject had been a teacherin a public school system and recalled experiencing the same symptomssubsequent to the use of inadequately ventilated duplication equipmentwhich required spirit fluid that contained over 50% methanol.

EXAMPLE 2

The male subject of EXAMPLE 1 consumed two grams of pure NUTRASWEET.There is over 1.7 grams of NUTRASWEET sweetener in a six pack of dietOrange Soda soft drink twelve ounce cans. The NUTRASWEET sweetener wasingested in four gelatin capsules. Within one hour after the two gramsof pure NUTRASWEET sweetener had been consumed, the subject wasexperiencing a headache and dizziness. A sample of the subject's bloodwas taken using the finger prick technique, excluding alcohol swabbingof the finger prior to lancing. The blood methanol concentration of thesubject had risen to over 1.5 parts per million. Samples of the subjectsblood were thereafter taken at thirty minute intervals. An hour and ahalf after consumption of the pure NUTRASWEET, the blood methanolconcentration peaked at two parts per million. Shortly after the bloodmethanol concentration peaked at two parts per million, the subjectcomplained of nausea and blurred vision. These symptoms, along with theheadache and dizziness, persisted for four hours prior to subsiding.After the symptoms had subsided, the methanol levels in the blood of thesubject were again undetectable.

The blood samples from the male subject were tested for methanol andethanol using a Varian Aerograph Model 3700 gas chromatograph equippedwith a flame ionization detector and a six foot×two millimeter interiordiameter glass column packed with a 60/80 Carbopack B coated withCarbowax 20M. The column was equipped with a precolumn and helium wasthe carrier gas at a flow rate of 20 ml/min. The whole blood sampleswere each diluted with an internal standard solution of n-propanol andinjected directly onto the column. The column was operated isothermallyat a temperature of 75° C. The peak areas were calculated by aHewlett-Packard 3390 A integrator. Under normal conditions, i.e., priorto consumption of NUTRASWEET sweetener, of methanol, or of ethanol, thelevel of ethanol and methanol in the subject's blood was undetectable.

EXAMPLE 3

Example 2 is repeated, except that the subject consumes a six pack ofdiet Orange Soda soft drink twelve ounce cans over one hour periodinstead of consuming two grams of pure NUTRASWEET sweetener. Similarresults were obtained.

EXAMPLE 4

Example 2 is repeated, except that the subject consumes two hundredmilliliters of a one gram per liter solution of methanol instead ofconsuming two grams of pure NUTRASWEET sweetener. The blood methanolconcentration of the subject peaked at 3.2 parts per million within onehalf hour after consumption of the solution. The symptoms of headache,dizziness, nausea and blurred vision occurred one hour after consumptionof the test liquid and subsided approximately two and one half hoursafter the solution of methanol was consumed.

EXAMPLE 5

The following are combined and heated until the solution clears and thesodium stearate dissolves:

Absolute ethanol: 84.00 grams

Sodium stearate: 4.40 grams

Water: 11.60 grams

No. 000 gelatin capsules are filled with the heated, clear solution andallowed to cool until the solution has jelled. The filled, cooledgelatin capsules are coated with a protective time release azopolymerfilm by dipping into a 15% Methylene chloride solution of a copolymer ofstyrene and hydroxyethylmethacrylate cross-linked with divinylazobenzeneand allowing the methylene chloride solvent to evaporate. The resultingazopolymer coating is, when the capsule is ingested, attacked by theindigenous microflora in the large intestines. The microflora reduce theazo bonds and allow the slow release of ethanol. The chloride copolymersolution is produced by mixing 140 grams of styrene, 860 grams ofhydroxyethylmethacrylate and 20 grams of divinylazobenzene and usingconventional methods to polymerize with twenty grams of benzoyl peroxideas the initiator. Unreacted monomers are removed by repeatedreprecipitation from chloroform solution by the addition of hexane.

EXAMPLE 6

Gelatin capsules are produced in accordance with EXAMPLE 5, except thatthe capsules are filled with an undiluted absolute ethanol solutioninstead of the warm, clear absolute ethanol--sodium stearate--watersolution of EXAMPLE 5.

EXAMPLE 7

No. 000 gelatin capsules are filled with the warm, clear absoluteethanol--sodium stearate--water solution of EXAMPLE 5. After thesolution has jelled, the gelatin capsules are transferred to a coatingpan and coated with cellulose acetate phthalate. Seven coats ofcellulose acetate phthalate are applied and standard USP DisintegrationTesting Apparatus is used to test the quality of the coatings.

EXAMPLE 8

The warm, clear absolute ethanol--sodium stearate--water solution ofEXAMPLE 5 is prepared and used to fill sacks made from Dialyzer tubing.After the water solution has cooled and jelled, the Dialyzer tubingsacks are coated with a protective time release azopolymer film in themanner described in EXAMPLE 5.

EXAMPLE 9

Sacks made from Dialyzer tubing are filled with an undiluted absoluteethanol solution. The Dialyzer tubing sacks are coated with a protectivetime release azopolymer film in the manner described in EXAMPLE 5.

EXAMPLE 10

Sacks made from Dialyzer tubing are filled with an undiluted absoluteethanol solution. The Dialyzer tubing sacks are coated with celluloseacetate phthalate in the manner described in EXAMPLE 7.

EXAMPLE 11

500 grams of polygalacturonide obtained from citrus pectin and 1500grams of absolute ethyl alcohol are refluxed under pressure at 65° C.rather than at the reflux temperature of ethanol. After ninety hours thepolyethyl compound left after evaporation of the ethanol contains about11.7% ethoxy group and is about 50% esterified. The polyethyl compoundcan be administrated as an ethanol source in place of the absoluteethanol--sodium stearate--water solution of EXAMPLE 5.

EXAMPLE 12

A 43 year old male subject was selected. The subject was five feet seveninches high, weighed 220 pounds, was i good health and was not takingany prescription drugs or other medications. The ethanol and methanollevels in the subject were tested using the blood sampling process ofExample 2. There initially were no detectable levels of ethanol andmethanol in the blood stream. The subject consumed at one sitting fourof the ethanol capsules produced in the manner described in EXAMPLE 5.Three hours later the subject consumed two grams of NUTRASWEETsweetener. After consuming the four capsules, the subject's blood wastested at hour intervals for concentration levels of ethanol andmethanol. The ethanol level in the subject's blood peaked at 14.6 partsper million three hours after ingestion of the four ethanol capsules.Eight hours after the capsules were ingested, the ethanol concentrationin the blood was 5.7 parts per million. Six hours after the NUTRASWEETwas consumed, the concentration of blood methanol was undetectable. Atno time did the subject experience headache, dizziness, nausea, and/orvision blurring.

EXAMPLE 13

The process of EXAMPLE 12 is repeated, except that four ethanol No. 000gelatin capsules filled with 1 gram/liter aqueous methanol solution areutilized. Similar results are obtained, with the maximum level ofmethanol in the blood being 3.9 ppm.

EXAMPLE 14

The process of EXAMPLE 2 is repeated, except that the subject is a 23year old female who is in good health, has a height of five feet oneinch, weighs one hundred pounds, and is not taking any prescriptiondrugs or other medication. Similar results are obtained.

EXAMPLE 15

The process of EXAMPLE 12 is repeated except that only two ethanolcapsules are consumed by the subject. Similar results are obtained.

EXAMPLE 16

The process of EXAMPLE 12 is repeated except that five to twenty ethanolcapsules are consumed by the subject. Similar results are obtained.

EXAMPLE 17

The process of EXAMPLE 12 is repeated except that six cans of twelveounce diet soft drink beverage containing a total of 1.7 grams ofNUTRASWEET are consumed instead of the two grams of pure NUTRASWEET. Thecans are consumed over a period of one hour. Similar results areobtained.

EXAMPLE 18

The process of EXAMPLE 12 is repeated, except that the subject is a 27year old female who is in good health, has a height of five feet threeinches, weigh one hundred and ten pounds, and is not taking anyprescription drugs or other medication. Similar results are obtained.

EXAMPLE 19

The process of EXAMPLE 12 is repeated, and when the levels of methanoland ethanol in the blood are tested, the levels of formaldehyde andformic acid, the metabolites of methanol, are also tested. The levels offormaldehyde and formic acid are undectable during all blood tests.

EXAMPLE 20

The process of EXAMPLE 2 is repeated, and when the level of methanol inthe blood is tested, the levels of formaldehyde and ethanol in the bloodare tested. One hour after the NUTRASWEET is consumed levels offormaldehyde and formic acid in the blood stream are not detectable.

EXAMPLE 21

The process of EXAMPLE 12 is repeated, except that a sugar or starchfermented in the presence of yeast is used in place of the absoluteethanol--sodium stearate--water solution to provide a source of ethanol.Similar results are obtained.

EXAMPLE 22

The process of EXAMPLE 12 is repeated, except that fermented blackstrapmolasses is used in place of the absolute ethanol--sodiumstearate--water solution to provide a source of ethanol. Similar resultsare obtained.

EXAMPLE 23

The process of EXAMPLE 12 is repeated, except that fermented potatoes ora fermented grain is used in place of the absolute ethanol--sodiumstearate--water solution to provide a source of ethanol. Similar resultsare obtained.

The EC 1.7.3.3 designation earlier used herein to describe the uricaseenzyme is an official international designation utilized todifferentiate enzymes.

Ethanol derived from petroleum products can also be utilized in thepractice of the invention.

The dietary vaccine of the invention can be ingested with or after theingestion of methanol or of substances which are metabolized intomethanol by the body. Maintaining a concentration of at least one ppmethanol in the blood stream appears to generally prohibit metabolism ofmethanol by the body. Preferably, the vaccine is ingested prior to theingestion of methanol or a methanol producing substance so that aconcentration of ethanol of at least one ppm can be established in theblood stream to protect an individual against the metabolism of methanolby his body.

As utilized herein, absolute ethanol indicates grain alcohol which hasbeen passed over a molecular sieve Grade 512 Type 4A (4-8 mesh)distributed by Matheson, Coleman and Bell Company. The molecular sievemarkedly reduces the amount of methanol and water in the grain alcohol.

Having described my invention in such terms as to enable those skilledin the art to understand and practice it, and having identified thepresently preferred embodiments and best mode thereof, I claim:
 1. Adietary vaccine introduced in the digestive tract of an individual toinhibit the metabolism of methanol by the human body to formformaldehyde and formic acid, said dietary vaccine comprising, incombination,(a) at least one source of ethanol selected from the classconsisting of ethyl alcohol and a polyethyl compound, said polyethylcompound being obtained by reflexing polygalacturonide and absoluteethyl alcohol; and, (b) gelatin capsule carrier means for said source ofethanol, said carrier means, when introduced in the digestive tract of ahuman being, permitting, while said carrier means moves along at least aselected portion of said digestive tract, the continuous release ofethanol from said carrier means into said digestive tract for absorptioninto the blood system of the individual in minor effective amountssufficient tomaintain a concentration of ethanol in the blood stream ofless then two hundred and fifty parts per million ethanol, inhibit themetabolism of methanol by the body, and avoid intoxication of saidindividual by said ethanol.
 2. The dietary vaccine of claim 1 whereinsaid gelatin capsule is coated with a coating reducible by indigenousmicroflora in the large intestines of an individual.
 3. The dietaryvaccine of claim 2 wherein said coating comprises a methylene chloridesolution of a copolymer of styrene and hydrozyethylmethacrylatecross-linked with divinylazobenzene.